The long-term objectives are to develop novel histamine H3 receptor antagonists to increase wakefulness, attention and enhance cognitive abilities. The specific aims of this grant are (1) to test a novel non- thiourea H3 antagonist, GT-2016, for its ability to increase histamine release in various rat brain regions, including the frontal and parietal cortex, hippocampus, corpus striatum and hypothalamus (2) to determine if GT-2016 possesses cognition-enhancing properties in normal juvenile and adult rats (3) to produce an attention deficit disorder (ASS) juvenile rat pup model and evaluate the cognitive impairments in this model (4) to determine if GT-2016 reverses the cognitive deficits in a rat model of ADD. The first aim will provide information on the regional specificity of GT-2016 on histamine turnover. The subsequent aims are to demonstrate the cognition enhancement of GT-2016 in juvenile and young adult normal rats. The third aim will use postnatal intracisternal administration 6-OHDA, five days following birth, to produce a selective loss in dopaminergic neurons. These animals will be tested for hyperactivity and cognitive deficits and reversal of the deficits will then be determined for GT-2016. Data generated from this research could identify the use of H3 antagonists in the treatment of cognitive disorders including ADD. PROPOSED COMMERCIAL APPLICATION: A novel H3 antagonist, GT-2016, will be tested for its effects on brain histamine release and cognitive enhancing properties in normal rats and an animal model of ADD.